TY - JOUR
T1 - IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation
AU - Nishimura, Shiho
AU - Kobayashi, Yoshiyuki
AU - Ohnishi, Hidenori
AU - Moriya, Kunihiko
AU - Tsumura, Miyuki
AU - Sakata, Sonoko
AU - Mizoguchi, Yoko
AU - Takada, Hidetoshi
AU - Kato, Zenichiro
AU - Sancho-Shimizu, Vanessa
AU - Picard, Capucine
AU - Irani, Sarosh R.
AU - Ohara, Osamu
AU - Casanova, Jean Laurent
AU - Puel, Anne
AU - Ishikawa, Nobutsune
AU - Okada, Satoshi
AU - Kobayashi, Masao
N1 - Funding Information:
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (16H05355 and 19H03620 to SO), Promotion of Joint International Research from the Japan Society for the Promotion of Science (18KK0228 to SO), and the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and development, AMED (to SO). SRI is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants- Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS-Society research award) and by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health). Acknowledgements
Funding Information:
The sequence analysis was supported by the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University. We thank to Kohsuke Imai (Tokyo Medical Dental University) and Michael Ciancanelli (Turnstone Biologics) for the assistance.
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
AB - IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.
KW - HHV6
KW - IRAK4
KW - anti-NMDAR encephalitis
KW - autoimmunity
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U2 - 10.1007/s10875-020-00885-5
DO - 10.1007/s10875-020-00885-5
M3 - Article
C2 - 33083971
AN - SCOPUS:85092899058
VL - 41
SP - 125
EP - 135
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
SN - 0271-9142
IS - 1
ER -